PROJECTI SUMMARY Project 1: Structural Analysis of HIV Entry Inhibition Our overall objective is to provide an atomic-level understanding of opportunities for intervention in processes of cell entry by HIV. We plan to continue our structural studies on HIV gpl20 in the context of this program project on antagonism of HIV envelope function in cell entry. Our technical focus is on x-ray crystallography, so as to determine structures at sufficient resolution to develop mechanistic insights, but associated binding experiments and computations will also be performed. Our aims include using crystal structure to screen for new lead compounds, structural analyses of complexes of HIV gp120 with candidate inhibitory molecules, structural studies of HIV gpl20 interactions with other natural binding partners besides CD4, and innovative computational analyses of gp 120 plasticity. We build not only on our recent experience in this project, but also on our earlier structural investigations of CD4, HIV gp120s, and associated antibodies. We have adopted or developed both appropriate expression systems for making the required proteins and also appropriate assays for following inhibitory action. We interact with all other elements of the program project: most intimately with Project 3 on chemistry (Smith) and Project 5 on virology (Sodroski), but also significantly with Project 2 on peptidomimetics and miniproteins (Chaiken), Project 4 on thermodynamics (Freire), prospectively with Project 6 on dynamics by single-molecule FRET (Mothes), and importantly with the computation core (LaLonde).